Clarifying the molecular mechanism associated with carfilzomib resistance in human multiple myeloma using microarray gene expression profile and genetic interaction network

Abstract

Carfilzomib is a Food and Drug Administration-approved selective proteasome inhibitor for patients with multiple myeloma (MM). However, recent studies indicate that MM cells still develop resistance to carfilzomib, and the molecular mechanisms associated with carfilzomib resistance have not been studied in detail. In this study, to better understand its potential resistant effect and its underlying mechanisms in MM, microarray gene expression profile associated with carfilzomib-resistant KMS-11 and its parental cell line was downloaded from Gene Expression Omnibus database. Raw fluorescent signals were normalized and differently expressed genes were identified using Significance Analysis of Microarrays method. Genetic interaction network was expanded using String, a biomolecular interaction network JAVA platform. Meanwhile, molecular function, biological process and signaling pathway enrichment analysis were performed based on Gene Ontology and Kyoto Encyclopedia of Genes and Genomes. Totally, 27 upregulated and 36 downregulated genes were identified and a genetic interaction network associated with the resistant effect was expanded basing on String, which consisted of 100 nodes and 249 edges. In addition, signaling pathway enrichment analysis indicated that cytokine–cytokine receptor interaction, autophagy, ErbB signaling pathway, microRNAs in cancer and fatty acid metabolism pathways were aberrant in carfilzomib-resistant KMS-11 cells. Thus, in this study, we demonstrated that carfilzomib potentially conferred drug resistance to KMS-11 cells by cytokine–cytokine receptor interaction, autophagy, ErbB signaling pathway, microRNAs in cancer and fatty acid metabolism pathways, which may provide some potential molecular therapeutic targets for drug combination therapy against carfilzomib resistance.

Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy

“…Proteasome inhibitors has been widely used as clinical anticancer drugs for the bone marrow cancer multiple myeloma (MM) and exhibited remarkable efficacy in solid tumor malignancies treatment, including the first-in-class proteasome inhibitor bortezomib and second-in-class proteasome inhibitors carfilzomib and oprozomib (Saavedra-García et al, 2020). However, increasing studies indicate that cancer cells show resistance to the proteasome inhibitors and autophagy contributes to the mechanisms associated with carfilzomib and bortezomib resistance (Zang et al, 2012;Zheng et al, 2017). CQ and HCQ can enhance carfilzomib induced cell apoptosis by inhibition of autophagy toward MM (Jarauta et al, 2016;Baranowska et al, 2016).…”

A predicted risk score based on the expression of 16 autophagy‑related genes for multiple myeloma survival

“…Autophagy has an important role in the pathogenesis of plasma cell development and MM, the incidence rate of which is estimated to be 2-3/100,000, and which mostly affects patients >40 years old (29)(30)(31). Generally, autophagy is considered to be involved in pro-survival mechanisms of MM cells and to interact with the ubiquitin-proteasome system to maintain homeostasis of MM cells via degraded and misfolded proteins for energy recovery (32)(33)(34)(35)(36). Therefore, inhibiting autophagy may effectively induce MM cell death and can act synergistically using proteasome inhibitors.…”

“…However, exaggerated activation of autophagy may result in excessive degradation A predicted risk score based on the expression of 16 autophagy-related genes for multiple myeloma survival of organelles, which can induce autophagic cell death. Thus, activation of autophagic cell death may represent a promising approach for treatment of MM (32)(33)(34)(35)(36). Recent studies have demonstrated that autophagy mediates drug resistance in MM cells and leads to development of clinical complications for MM, while inhibition of autophagy may reverse the response to drugs (37,38).…”

Characterization of carfilzomib-resistant non-small cell lung cancer cell lines

“…Therefore, cells that are initially highly sensitive to CFZ because of low Pgp may have the potential to become highly resistant once Pgp upregulation occurs. In addition to Pgp, gene profiling has identified additional adaptive changes in the CFZ-resistant cells compared to parental cells (Mitra et al 2017;Riz et al 2015;Riz et al 2016;Zheng et al 2017).…”